Bevacizumab Combination Chemotherapy Research Articles

Kras-mutation influences outcomes for palliative primary tumor resection in advanced colorectal cancer-a Turkish Oncology Group study

PurposeWe aimed to investigate the prognostic effect of primary tumor resection (PTR) prior to bevacizumab-based treatments in unresectable metastatic colorectal cancer (mCRC). MethodsWe retrospectively collected 341 mCRC cases with unresectable metastases at diagnosis. PTR was performed in 210 cases (the surgery group) and the other patients (n = 131) were followed without PTR (the no-surgery group). All the patients were treated with bevacizumab combined chemotherapy regimens. ResultsThe median progression free survival (PFS) of the surgery group was 10.4 months (95% CI: 8.9–11.9), which was significantly better than that of the no-surgery group (7.6 months, 95% CI: 6.4–8.8, P=0.000). The median overall survival (OS) of the surgery group was longer than that of the no-surgery group (27.4 months vs. 18.3 months, respectively, P=0.000). The median PFS and OS of the surgery group were 10.4 months and 28.2 months, which were significantly longer than that of the no-surgery group in Kras-mutant patients (7.8 months and 18.3 months; P=0.004, P=0.028, respectively). There was no difference in terms of PFS and OS between the surgery and the no-surgery groups in Kras-wild type patients. ConclusionPalliative PTR may improve the survival outcomes for unresectable mCRC patients. PTR may be preferred, particularly in Kras-mutant patients.

Bevacizumab-induced intestinal perforation in a patient with inoperable breast cancer: a case report and review of the literature

BackgroundGastrointestinal perforation is known as a serious adverse event, but, for breast cancer, there are very few reports of gastrointestinal perforation. This report highlights gastrointestinal perforation caused by bevacizumab for breast cancer, which is of special interest because gastrointestinal perforations caused by bevacizumab are very rare in breast cancer.Case presentationWe describe the case of 54-year-old Japanese woman. She was diagnosed as having inoperable breast cancer T2 N1 M1 (pleura, peritoneum), Stage IV, and received chemotherapy by paclitaxel. There was reduction in the primary tumor and disappearance of the pleural effusion; however, the ascites did not change. We performed diagnostic laparoscopy which revealed that her whole peritoneum was thickened, and her small intestine, colon, and her omentum were grouped and formed an omental cake. We submitted a part of her peritoneum to pathological examination and diagnosed the peritoneum dissemination of breast cancer. On the basis of these results, paclitaxel and bevacizumab combination chemotherapy was started, and a decrease in ascites was seen. However, a gastrointestinal perforation occurred on 26th day of second cycle of bevacizumab + paclitaxel, and we performed an emergency operation. In the operation, the omental cake was resolved, and we could search the full length of the gastrointestinal tract. Two small perforations of her small intestine were seen. We performed simple closures for perforations, and peritoneal lavage and drainage. She was in a state of septic shock, but it improved. It was thought that the small intestinal perforations were caused by the bevacizumab-additional chemotherapy which was very effective.ConclusionsWe report a very rare and valuable case. This case suggests that the risk of gastrointestinal perforation must be considered in a case of bevacizumab administration, and it is necessary to determine carefully the patient administered bevacizumab, regardless of the type of cancer.

A Case of Acute Pulmonary Thromboembolism during Bevacizumab Combination Chemotherapy for Lung Adenocarcinoma

A Case of Acute Pulmonary Thromboembolism during Bevacizumab Combination Chemotherapy for Lung Adenocarcinoma

KRAS mutation and primary tumor location do not affect efficacy of bevacizumab-containing chemotherapy in stagae IV colorectal cancer patients

This study aims to investigate the efficacy of bevacizumab-combined chemotherapy (BCC) in Chinese stage IV colorectal cancer (CRC), and analyze the relationship between clinicopathological features with survival. Patients with stage IV CRC treated with BCC were analyzed retrospectively. 217 metastatic CRC (mCRC) patients were collected, out of which79 were right-sided CRCs and 138 were left-sided ones. Patients with Eastern Cooperative Oncology Group (ECOG) performance status ≤2, single agent chemotherapy, poor/mucous/signet ring cell component, second-and further-line of bevacizumab administration, multiple metastasis sites had comparatively worse survival. Among 141 patients with known KRAS status, 55 patients harbored KRAS mutation and 86 had wild type KRAS. The ORR and DCR were 41.9% and 78.9%, respectively, in patients with wild type KRAS, while ORR and DCR was 38.7% and 77.9%, respectively, in patients with KRAS mutation. The median PFS of patients with wild type and mutant KRAS were 8.38, and9.59 months, respectively; whereas the OS was 23.00 and 21.26 months, respectively for mCRC patients with wild-type and mutant KRAS. Cumulatively, our study indicated that BCC was effective and beneficial for Chinese stage IV CRC patients. KRAS mutation status and tumor location were not a prognostic factor for survival.

Subserous invasion of VEGF-C-producing cancer cells is a possible risk factor for ileal ulceration in the non-metastatic mucosal layer during bevacizumab-combined chemotherapy for recurrent ovarian cancer: A case report.

A 65-year-old woman received chemotherapy using taxane and carboplatin prior and following optimal debulking surgery for ovarian cancer stage IV. Five months later, intra-abdominal recurrence was diagnosed, and second-line chemotherapy using nogitecan and bevacizumab was administered. After five courses, the patient presented with a symptom of subileus and subsequent intestinal perforation occurred. An emergent surgery revealed two perforation sites and longitudinally extended ulcerative lesions in the ileum. Pathologically, although metastatic sites were not observed in the submucus layer just beneath the ulcers, there were a number of vascular endothelial growth factor (VEGF)-C-positive cancer cell invasion sites along with marked edema and an increase of the lymphatic endothelial cell marker ‘podoplanin’-positive cells in subserous regions. Since bevacizumab is able to inhibit VEGF-A, but not VEGF-C, and induce compensatory increase in VEGF-C production, these findings suggest that the local disturbance of lymphatic circulation in the subserous regions by VEGF-C-producing cancer cells is a possible risk factor for the development of intestinal ulceration and perforation during bevacizumab therapy.

Soluble CD87 (s-uPAR) predicts bevacizumab-based first line treatment of metastatic colorectal cancer (mCRC): Results from a prospective multi-center study.

604 Background: Bevacizumab-combined chemotherapy is well established in the induction treatment of metastatic colorectal cancer (mCRC). Despite tremendous efforts, no valid predictive marker for anti-VEGF treatment has so far been defined. CD87, the urokinase plasminogen activator receptor (uPAR), is centrally regulating VEGF-induced angiogenesis via adapting endothelial cell migration and invasion (Unseld et al.; ThrombHaem,2015, Brunner et al.; Blood 2011, Prager et al; Blood 2009; Prager et al; Blood 2004). Preoperative plasma s-uPAR levels were shown to independently predicted survival of patients resectable colorectal cancer. This study aimed to identify any prognostic or predictive value of s-uPAR in front-line bevacizumab-treated mCRC patients. Methods: In this prospective multi-center trial (NCT02119026), patients were either treated with bevacizumab plus FOLFOX or bevacizumab plus FOLFIRI. Baseline s-uPAR levels were assessed in 80 patients (40 ea. group) using respective CE-certified electro-chemiluminescence immunoassay (ECLIA). Biomarkers were explored using Kaplan-Meier curves and were log transformed for survival analysis by Cox proportional hazards models. All P values reported are two-sided. Results: Data from eighty patients were available for analysis. Progression free survival (PFS) and overall survival (OS) were assessed. Data indicate significance for the angiogenic biomarker uPAR to determine prognostic (HR = 3.06, CI 1.45 - 6.53, p = 0.003) and predictive (HR = 3.41, CI 2.03 - 5.74, p < 0.001) value in the treatment of Bevacizumab. Conclusions: This is the first prospective analysis of baseline s-uPAR. High baseline-s-uPAR levels were an independent predictive marker for worse bevacizumab-based first-line treatment response.

Maintenance of Clinical Expertise and Clinical Research by the Clinical Professors at Gifu Pharmaceutical University.

The clinical professors at Gifu Pharmaceutical University (GPU) provide pharmaceutical services at GPU Pharmacy, Gifu University Hospital, and Gifu Municipal Hospital to keep their clinical skills up-to-date; they also perform clinical research in collaboration with many clinical institutes. The Laboratory of Clinical Pharmacy is part of the Department of Pharmacy Practice and Science, to which the clinical professors belong, and is composed of three clinical professors (a professor, an associate professor, and an assistant professor). The professor administers the GPU Pharmacy as its director, while the associate professor and assistant professor provide pharmaceutical services to patients at Gifu Municipal Hospital, and also provide practical training for students in the GPU Pharmacy. Collectively, they have performed research on such topics as medication education for students, clinical communication education, and analysis of clinical big data. They have also conducted research in collaboration with clinical institutes, hospitals, and pharmacies. Here, we introduce the collaborative research between the Laboratory of Clinical Pharmacy and Gifu Municipal Hospital. These studies include "Risk factors contributing to urinary protein expression resulting from bevacizumab combination chemotherapy", "Hyponatremia and hypokalemia as risk factors for falls", "Economic evaluation of adjustments of levofloxacin dosage by dispensing pharmacists for patients with renal dysfunction", and "Effect of patient education upon discharge for use of a medication notebook on purchasing over-the-counter drugs and health foods". In this symposium, we would like to demonstrate one model of the association and collaborative research between these clinical professors and clinical institutes.

Phase II study of irinotecan and bevacizumab plus alternate day S-1 as second-line treatment in patients with metastatic colorectal cancer.

749 Background: The recommended dose of combination chemotherapy of irinotecan, bevacizumab and oral S-1 is 100mg/m2, 5mg/kg and 80-120mg/body respectively. To evaluate whether the dose of irinotecan could be raised to 150mg/m2 with modified administration of S-1, we have conducted a phase II study of irinotecan and bevacizumab plus alternate day S-1 in patients with metastatic colorectal cancer (UMIN000008947). Methods: Patients with metastatic colorectal cancer after failure with first-line treatment of oxaliplatine and fluoropyrimidine were enrolled. Irinotecan (150 mg/m2) and bevacizumab (5mg/kg) were given intravenously on day 1. Oral S-1was administered on alternate days at a dose of 40-60mg twice a day. Cycles were repeated every two weeks. Results: A total of 51 patients were evaluated in the first fouur cycles. Grade 3 and 4 neutropenia were 10% (10/51) and 13.7%(7/10), grade 3 and 4 thrombocytopenia were 0%(0/51) and 2.0% (1/51). Grade 2 and 3 mucositis were 13.7% (7/51) and 3.9% (2/51). Grade 2 and 3 nausea were 11.8% (6/51) and 2.0% (1/51). Grade 2 and 3 diarrhea were 17.6% (9/51) and 15.7% (8/51). The relative dose intensities were 84.8% for irinotecan, 87.5% for bevacizumab, and 84.8% for S-1 respectively in the first four cycles. Conclusions: Our data suggest that irinotecan (150 mg/m2) and bevacizumab was administered safely with alternate day S-1 as second-line tratment in patients with metastatic colorectal cancer. Clinical trial information: 000008947.

Observational cohort study of first-line bevacizumab with oxaliplatin or irinotecan and fluoropyrimidines in metastatic colorectal cancer: HGCSG0802—Analysis of early tumor shrinkage (ETS).

753 Background: It was reported that early tumor shrinkage (ETS) was associated with better overall survival (OS) in patients (pts) with metastatic colorectal cancer (mCRC) receiving first line chemotherapy. We investigated association of ETS with progression-free survival (PFS) and OS in pts with mCRC treated with first-line bevacizumab (BV)-based chemotherapy (HGCSG0802). Methods: The objective of HGCSG0802 was to evaluate PFS, OS, response rate (RR), safety and so on. The key eligibility criteria were evaluable lesions, older than 20 years old, ECOG PS 0-2. This analysis evaluated the association of ETS at 8 weeks from the start of chemotherapy with pts characteristics, PFS and OS. To identify factors associated with ETS, if there were clinical variables with p < 0.2 in univariate analysis, we planned a multivariate analysis using the logistic regression model. To identify predictive and prognostic factors, a multivariate analysis was performed using Cox proportional hazard model with backward elimination for variables with p < 0.2 in univariate analysis. Results: Of 108 pts (the full analysis set), 99 pts were evaluable for ETS. Sixty-eight pts (68.7%) had ETS ≥20%. The pts characteristics between ETS ≥20% (ETS) and <20% (Non-ETS) were well balanced. In univariate analysis to identify factors associated with ETS, there were no clinical variables with p < 0.2. The median PFS and OS were 7.3/18.3 months in Non-ETS versus 10.0/25.2 months in ETS (HR 0.529; p=0.006 and HR 0.627; p=0.107). In multivariate analysis for PFS and OS, although there was no significant difference between ETS and Non-ETS for OS (HR 0.709; p=0.186), there was significant difference for PFS (HR 0.524; p=0.006). Conclusions: ETS was observed in 68.7% (68/99) and non-ETS in 31.3% (31/99) of patients with metastatic colorectal cancer received bevacizumab combined first line chemotherapy. In univariate analysis, it could not identify any factors associated with ETS. In the results of multivariate analysis, ETS showed an independent predictive impact, but not prognostic impact. Clinical trial information: UMIN000018935.

Observational cohort study of 1st line bevacizumab combined with chemotherapy in metastatic colorectal cancer (HGCSG0802): Sub-group analysis by the GERCOR index.

743 Background: The GERCOR index based on performance status and serum LDH was reported to be useful to predict survival for patients with previously untreated mCRC. However, the validity of the GERCOR index has not been reported in patients treated with bevacizumab (Bev)-based first line chemotherapy. Methods: 115 patients with mCRC treated with Bev contained first line chemotherapy were registered from 15 centers in Japan. Univariate and multivariate analysis for overall survival (OS) were performed using patient characteristics. Survival analyses were performed with the Kaplan-Meier method, log-rank test and the Cox proportional hazards model. The analysis was also designed to determine whether the GERCOR index could be extended to progression-free survival (PFS). Results: All data were available for prognostic categorization in 108 patients. Patients with the GERCOR index of low, intermediate and high risk were 45, 57, and 6, respectively. The pts characteristics between low risk (L) and intermediate/high risk (I/H) were generally balanced except for prior colorectomy (75.6% in L, 54.0% in I/H; p = 0.027), based cytotoxic agent (oxaliplatin) (80.0% in L, 93.7% in I/H; p = 0.039), liver metastasis (53.3% in L, 79.4% in I/H; p = 0.006) and median number of metastatic organ (1 in L, 2 in I/H; p = 0.024). The distribution and median OS / PFS for the GERCOR index were as follows: L (n = 45; 29.9/10.0 months), I/H (n = 63; 17.0/8.5 months). For OS, there was significant difference between L and I/H (p = 0.003). For PFS, there was not significant difference between L and I/H (p = 0.522). In the Cox multivariate analysis, GI did not show an independent prognostic impact (L vs I/H ; HR 1.499, p = 0.120) and predictive impact (L vs I/H ; HR 0.922, p = 0.733). Conclusions: In this analysis, the GERCOR index might be neither the predictive nor prognostic factor in the bevacizumab combined first line chemotherapy for patients with mCRC.

Updated analysis: Observational cohort study of first-line bevacizumab combined with chemotherapy in metastatic colorectal cancer (HGCSG0802)—Sub-group analysis by KRAS Exon2 status.

522 Background: A few reports have shown the efficacy of bevacizumab (BV) independent of the KRAS Exon2 mutational status (KRAS). We performed a sub-group analysis by KRAS from the HGCSG0802 observational cohort study that investigated 115 patients (pts) treated with 1st line BV for metastatic colorectal cancer (mCRC). Methods: The objective of HGCSG0802 was to evaluate progression-free survival (PFS), overall survival (OS), response rate (RR), and safety. The key eligibility criteria were with evaluable lesions, older than 20 years, ECOG PS 0-2. In this analysis, pts characteristics, RR and safety were compared using Fisher’s exact test. Univariate and multivariate analysis for PFS and OS were performed using patient characteristics. Survival analyses were performed with Kaplan-Meier method and Cox proportional hazards model. Results: Of 108 pts (the full analysis set), 99 pts were evaluable for KRAS. Sixty-two pts (62.6%) had KRAS wild-type (wt) and 37 pts (37.4%) had mutation (mt). The pts characteristics between those with wt and with mt were generally balanced except for PS 0 (91.9% in wt, 75.7% in mt; p = 0.036) and lung metastasis (33.9% in wt, 62.2% in mt; p = 0.007). RR was 70.0% in wt versus 65.7% in mt. Adverse events related to BV were almost balanced except for bleeding (any grade) (30.6% in wt, 13.5% in mt; p = 0.088). The median PFS and OS was 9.9 and 26.8 months in wt versus 7.9 and 17.5 months in mt (PFS ; HR 1.519, p = 0.064 and OS ; HR 1.944, p = 0.005). In Cox multivariate analysis, KRAS mt showed significantly shorter PFS and OS (PFS ; HR 1.637, p = 0.045 and OS ; HR 2.132, p = 0.005). Conclusions: In this cohort, depending on the KRAS Exon2 mutational status, severe adverse events were no significant difference. The multivariate analysis showed that PFS and OS were significantly longer in the KRAS Exon2 wild-type patients. So, KRAS Exon2 mutational status can be a predictive and prognostic marker in bevacizumab combined 1st line chemotherapy. Clinical trial information: UMIN000018935.

Primary Tumour Resection Could Improve the Survival of Unresectable Metastatic Colorectal Cancer Patients Receiving Bevacizumab-Containing Chemotherapy

Background: The effect of primary tumour resection (PTR) among metastatic colorectal cancer (mCRC) patients remains controversial. Combination chemotherapy with bevacizumab could improve the clinical outcomes of these patients, which might change the importance of PTR in the multi-disciplinary treatment pattern. Methods: We performed a non-randomized prospective controlled study of mCRC pts whose performance status (PS) scored ≤2 and who received bevacizumab combination chemotherapy (FOLFOX/XELOX/FOLFIRI) as a first-line therapy. These patients were classified into the PTR group and the IPT (intact primary tumour) group according to whether they underwent PTR before receiving the systemic therapy. The progression free survival (PFS) time and overall survival (OS) time, which were recorded from the start of the primary diagnosis until disease progression and death or last follow-up, were analysed. We also compared severe clinical events (such as emergency surgery, radiation therapy, and stent plantation) between the two groups. Results: One hundred and nighty-one mCRC pts (108 male patients and 93 female patients) were entered in this prospective observational study. The median age was 57.5 years old. The clinical characteristics (age, gender, performance status, primary tumour site, RAS status, and the number of metastatic organs) did not significantly differ between the two groups. The median PFS and OS times of the PTR group were superior than those of the IPT group (10.0 vs 7.8 months, p < 0.01 and 22.5 vs 17.8 months, p < 0.01, respectively). The incidences of adverse events associated with systemic therapy were similar between the two groups. Specifically, sixteen patients (21.9%, 16/73) with IPT developed significant primary tumour-related complications, such as bleeding, obstruction or even perforation. Among these patients, five underwent emergency surgery, three patients received a stent, and eight patients underwent radiation therapy. Conclusions: The mCRC patients who received PTR and bevacizumab combination chemotherapy had better clinical outcomes than patients who did not receive PTR. PTR also decreased the incidence of severe clinical events and improved quality of life.

Bevacizumab併用療法中に消化管穿孔をきたした手術不能乳癌の1例

症例は54歳の女性で，手術不能乳癌T2N1M1（PER，PLE），Stage IVと診断され，パクリタキセルが開始された．原発巣は縮小し，胸水は消失するも，腹水は減少せず，審査腹腔鏡を施行した．小腸・結腸・大網は一塊となり，腹膜は肥厚していた．腹膜の一部を病理組織学的検査に提出し，乳癌腹膜播種の所見であった．パクリタキセル・ベバシズマブ併用療法が開始され，腹水は減少したが，2コース目の26日目に消化管穿孔をきたし，開腹術を施行した．一塊となっていた腸管は癒着が解除され全検索が可能で，Treitz靱帯から120cmの小腸に穿孔を認め，単純閉鎖・腹腔内洗浄ドレナージを行った．術後は概ね良好に経過し，術後13日目に腫瘍内科転科となった．総合的に判断して，ベバシズマブが著効し，小腸穿孔をきたしたと考えられた．乳癌でのベバシズマブによる消化管穿孔は本邦初例であり，非常に貴重な症例を経験したので報告する．

ベバシズマブ併用化学療法施行中に後腹膜血腫をきたした進行直腸癌の１例

進行・再発結腸直腸癌に対するベバシズマブ併用化学療法施行中に後腹膜血腫をきたした１例を経験したので報告する．症例は60歳女性．下血を主訴に当院受診し諸検査にてT3N2M1 Stage Ⅳ直腸癌と診断された．XELOX＋ベバシズマブによる化学療法を３コース施行後，低位前方切除術を行い，その後再度XELOX＋ベバシズマブ療法を開始した．４コース目投与後８日目に頭痛と左側腹部痛を認め，CTにて左後腹膜血腫と診断された．入院の上保存的に加療し投与後15日目に退院となった．ベバシズマブ併用化学療法による合併症として重篤な出血は国内で0.6～1.4％，海外で３～６％と報告されているが，後腹膜血腫の報告はなく海外も含めて本症例が初報告例となる．出血の程度により重篤となりえるため留意すべき合併症と考えられる．

Response to bevacizumab combination chemotherapy of malignant pleural effusions associated with non-squamous non-small-cell lung cancer

Malignant pleural effusion (MPE) is a common complication of lung cancer with devastating consequences. Since vascular endothelial growth factor (VEGF) has been implicated in MPE, we hypothesized that bevacizumab, an anti-VEGF antibody, may be effective against MPE in patients with non-small-cell lung cancer (NSCLC). We analysed the records of 21 patients treated for NSCLC-associated MPE between February, 2010 and August, 2013 who consequently underwent bevacizumab combination chemotherapy at the Institute of Biomedical Research and Innovation Hospital. The results were retrospectively analysed using case records and radiographic imaging records. Three patients exhibited complete response of the pleural effusion to bevacizumab treatment, 8 patients achieved a partial response (PR) and 6 patients showed no response. When efficacy was assessed by the response of the measurable primary or metastatic lesions to the treatment, 5 patients achieved a PR, 13 patients had stable disease and 3 patients exhibited progressive disease. The response rate (RR) of the pleural effusion to the antibody treatment was 71.4% and the overall RR of measurable lesions was 23.8%. The median time-to-response for pleural effusion was 132 days. In conclusion, this study demonstrated a high R R to bevacizumab combination therapy for the MPE associated with non-squamous NSCLC. Therefore, bevacizumab therapy may be considered a therapeutic option for patients with non-squamous NSCLC who develop MPE.

Mean platelet volume as a prognostic marker in metastatic colorectal cancer patients treated with bevacizumab-combined chemotherapy.

Recent studies have revealed a prognostic impact of the MPV (mean platelet volume)/platelet count ratio in terms of survival in advanced non-small cell lung cancer. However, there has been no direct analysis of the survival impact of MPV in patients with mCRC. The aim of the study is to evaluate the pretreatment MPV of patients with metastatic and non-metastatic colorectal cancer (non-mCRC) and also the prognostic significance of pretreatment MPV to progression in mCRC patients treated with bevacizumab-combined chemotherapy. Fifty-three metastatic and ninety-five non-metastatic colorectal cancer patients were included into the study. Data on sex, age, lymph node status, MPV, platelet and platecrit (PCT) levels were obtained retrospectively from the patient medical records. The MPV was significantly higher in the patients with mCRC compared to those with non-mCRC (7.895±1.060 versus 7.322±1.136, p=0.013). The benefit of bevacizumab on PFS was significantly greater among the patients with low MPV than those with high MPV. The hazard ratio (HR) of disease progression was 0.41 (95%CI, 0.174-0.986; p=0.04). In conclusion, despite the retrospective design and small sample size, MPV can be considered a prognostic factor for mCRC patients treated with bevacizumab-combined chemotherapy.

Improved Survival With Bevacizumab in Advanced Cervical Cancer

Background Vascular endothelial growth factor (VEGF) promotes angiogenesis, a mediator of disease progression in cervical cancer. Bevacizumab, a humanized anti-VEGF monoclonal antibody, has single-agent activity in previously treated, recurrent disease. Most patients in whom recurrent cervical cancer develops have previously received cisplatin with radiation therapy, which reduces the effectiveness of cisplatin at the time of recurrence. We evaluated the effectiveness of bevacizumab and nonplatinum combination chemotherapy in patients with recurrent, persistent, or metastatic cervical cancer. Methods Using a 2-by-2 factorial design, we randomly assigned 452 patients to chemotherapy with or without bevacizumab at a dose of 15 mg per kilogram of body weight. Chemotherapy consisted of cisplatin at a dose of 50 mg per square meter of body-surface area, plus paclitaxel at a dose of 135 or 175 mg per square meter or topote can at a dose of 0.75 mg per square meter on days 1 to 3, plus paclitaxel at a dose of 175 mg per square meter on day 1. Cycles were repeated every 21 days until disease progression, the development of unacceptable toxic effects, or a complete response was documented. The primary end point was overall survival; a reduction of 30% in the hazard ratio for death was considered clinically important. Results Groups were well balanced with respect to age, histologic findings, performance status, previous use or nonuse of a radiosensitizing platinum agent, and disease status. Topotecan–paclitaxel was not superior to cisplatin–paclitaxel (hazard ratio for death, 1.20). With the data for the two chemotherapy regimens combined, the addition of bevaciz umab to chemotherapy was associated with increased overall survival (17.0 months vs. 13.3 months; hazard ratio for death, 0.71; 98% confidence interval, 0.54 to 0.95; P = 0.004 in a one-sided test) and higher response rates (48% vs. 36%, P = 0.008). Bevacizumab, as compared with chemotherapy alone, was associated with an increased incidence of hypertension of grade 2 or higher (25% vs. 2%), thromboembolic events of grade 3 or higher (8% vs. 1%), and gastrointestinal fistulas of grade 3 or higher (3% vs. 0%). Conclusions The addition of bevacizumab to combination chemotherapy in patients with recurrent, persistent, or metastatic cervical cancer was associated with an improvement of 3.7 months in median overall survival. (Funded by the National Cancer Institute; GOG 240 ClinicalTrials.gov number, NCT00803062.)

Improved Survival with Bevacizumab in Advanced Cervical Cancer

BackgroundVascular endothelial growth factor (VEGF) promotes angiogenesis, a mediator of disease progression in cervical cancer. Bevacizumab, a humanized anti-VEGF monoclonal antibody, has single-agent activity in previously treated, recurrent disease. Most patients in whom recurrent cervical cancer develops have previously received cisplatin with radiation therapy, which reduces the effectiveness of cisplatin at the time of recurrence. We evaluated the effectiveness of bevacizumab and nonplatinum combination chemotherapy in patients with recurrent, persistent, or metastatic cervical cancer.MethodsUsing a 2-by-2 factorial design, we randomly assigned 452 patients to chemotherapy with or without bevacizumab at a dose of 15 mg per kilogram of body weight. Chemotherapy consisted of cisplatin at a dose of 50 mg per square meter of body-surface area, plus paclitaxel at a dose of 135 or 175 mg per square meter or topotecan at a dose of 0.75 mg per square meter on days 1 to 3, plus paclitaxel at a dose of 175 mg per square meter on day 1. Cycles were repeated every 21 days until disease progression, the development of unacceptable toxic effects, or a complete response was documented. The primary end point was overall survival; a reduction of 30% in the hazard ratio for death was considered clinically important.ResultsGroups were well balanced with respect to age, histologic findings, performance status, previous use or nonuse of a radiosensitizing platinum agent, and disease status. Topotecan–paclitaxel was not superior to cisplatin–paclitaxel (hazard ratio for death, 1.20). With the data for the two chemotherapy regimens combined, the addition of bevacizumab to chemotherapy was associated with increased overall survival (17.0 months vs. 13.3 months; hazard ratio for death, 0.71; 98% confidence interval, 0.54 to 0.95; P=0.004 in a one-sided test) and higher response rates (48% vs. 36%, P=0.008). Bevacizumab, as compared with chemotherapy alone, was associated with an increased incidence of hypertension of grade 2 or higher (25% vs. 2%), thromboembolic events of grade 3 or higher (8% vs. 1%), and gastrointestinal fistulas of grade 3 or higher (3% vs. 0%).ConclusionsThe addition of bevacizumab to combination chemotherapy in patients with recurrent, persistent, or metastatic cervical cancer was associated with an improvement of 3.7 months in median overall survival. (Funded by the National Cancer Institute; GOG 240 ClinicalTrials.gov number, NCT00803062.)

Response to the first-line FOLFOX plus bevacizumab (BEV) therapy to predict responses to the subsequent therapies and survival in the BEV beyond progression (BBP) strategy for metastatic colorectal cancer: A retrospective analysis of CCOG-0801 study.

428 Background: The aim of this study was to evaluate the association of early tumor response to the first-line bevacizumab (BEV) combination therapy with efficacy of the subsequent therapies and survival during the BEV beyond progression (BBP) strategy for metastatic colorectal cancer (mCRC) patients. Methods: We analyzed a pooled data set from the previous phase II studies of mCRC, testing BBP strategy with the first-line mFOLFOX plus BEV (N=47) and the second-line FOLFIRI plus BEV (N=31). Patients were classified into either responders (R group, n=29) with tumor shrinkage (complete response [CR] + partial response [PR]), sub-responders (SR group, n=11) with stable disease (SD) and non-responders (NR group, n=5) with disease progression (PD) at the point of initial three months of the first-line therapy. The tumor response and PFS in the subsequent therapies and OS were evaluated. Results: In the first-line FOLFOX+BEV therapy, further tumor shrinkage was not achieved after the initial three months. PFS was 15.0 months for the R group, 8.9 months for the SR group and 2.9 months for the NR group, respectively, and there was statistical significance favoring the R group (p=0.001). In the second-line FOLFIRI+BEV, RR and DCR were 39 and 78% in the R group, 14 and 57% in the SR group, and 0 and 0% in the NR group, respectively. No additional response to the first-line therapy was observed in all groups, except for only one patient in the SR group. PFS was 8.8 months for the R group, 6.0 months for SR group and 1.4 months for NR group, respectively, and the R group was significant predictor for prolonged PFS in the second-line setting. OS were 30.8 months for the R group, 24.7 months for the SR group, and 11.1 months for the NR group, respectively. Early disease control (R+SR) was significant predictor for OS (hazard ratio [HR]: 8.48, p&lt;0.01) in multivariate analysis. Conclusions: These findings indicate that the tumor response within initial three months of first-line BEV combination chemotherapy could predict efficacies of subsequent treatments and OS in the BBP strategy for mCRC patients. Clinical trial information: UMIN000006818.

Bevacizumab combined with chemotherapy in the treatment of recurrence or platinum-refractory ovarian cancer: a retrospective study of 37 cases.

Ovarian cancer was one of the most diagnostic cancers for women and leading cause of death from gynecologic cancer. Most of the cases were at advanced stage when diagnosed. Platinum-based regimen was considered as the firs-line chemotherapy treatment modality. But most of the cases developed recurrence or resistance to platinum. The aim of this retrospective study was to evaluate the activity and toxicity of bevacizumab combined with chemotherapy in the treatment of recurrence or platinum-refractory ovarian cancer. Totally, 37 ovarian cancer patients with complete data who treated with bevacizumab combined with chemotherapy were reviewed from the databases of Beijing Cancer hospital and included in this retrospective study. All included patients received >1 cycle of bevacizumab based combination therapy with eligible for the efficacy and toxicity assessments. The objective response rate (ORR) and toxicity were recorded and evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) National Cancer Institute's Common Toxicity Criteria. The ORR and disease control rate were 32.4% and 54.1% respectively by the RECIST criteria and 43.2%, 67.6% by CA125 criteria. The median progression-free survival for the 37 cases was 5.4 months with its range of 2.3-11.2 months. The two complete response patens had longest disease-free survival interval with one for 10.0 months and another for 11.2 months. The total grade III-IV hematologic toxicity and nonhematologic toxicity were 8.1% and 21.6% respectively. With acceptable toxicity and relative well clinical activity, the bevacizumab combined chemotherapy can be a potential treatment modality for the recurrent or platinum-refractory ovarian cancer.